63: Miscellaneous Antihypertensives and Pharmacologically Related Agents

Jerome DeRoos Francis

INTRODUCTION

Hypertension is one of the commonest chronic medical problems and one of the most readily amenable to pharmacotherapy. Beginning in the 1960s, when asymptomatic hypertension was linked to significant adverse effects such as stroke, myocardial infarction, and sudden death, antihypertensive pharmacotherapeutics began being used. The first generation included centrally acting, sympatholytics, direct vasodilators, sodium nitroprusside, and diuretics. Unfortunately, these often had significant adverse events, leading to the development of β-adrenergic antagonists, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and, more recently, direct renin inhibitors (DRIs). This chapter reviews the first-generation antihypertensives, as well ACEIs, ARBs, and DRIs. In general, the majority of antihypertensives manifest clinical signs and symptoms in terms of the degree of hypotension produced. Particular attention will be placed on mechanisms of action and unique toxicologic considerations for each of these xenobiotics.

CLONIDINE AND OTHER CENTRALLY ACTING ANTIHYPERTENSIVES

Clonidine is an imidazoline compound that was synthesized in the early 1960s. Because of its potent peripheral α2-adrenergic agonist effects, it was initially studied as a potential topical nasal decongestant. However, hypotension was a common adverse event, which redirected its consideration for other therapeutic applications.105 Clonidine is the best understood and the most commonly used of all the centrally acting antihypertensives, a group that includes methyldopa, guanfacine, and guanabenz. Although these drugs differ chemically and structurally, they all decrease blood pressure in a similar manner. The imidazoline compounds oxymetazoline and tetrahydrozoline, which are used as ophthalmic topical vasoconstrictors and nasal decongestants, produce similar systemic effects when ingested.105

Since 1985, the increased efficacy and improved adverse event profiles of the newer antihypertensives have diminished the use of the α2-adrenergic agonists in routine hypertension management. However, their use is increasing as a result of a wide variety of applications, including attention-deficit/hyperactivity disorder (ADHD), peripheral nerve and spinal anesthesia, and as an adjunct in the management of opioid, ethanol, and nicotine withdrawal.120,127,130,224 In addition, abuse of clonidine may be a growing problem in opioid dependent patients, and it has been used in criminal acts of chemical submission.20,145 Although centrally acting α2-adrenergic agonist exposure is relatively uncommon, it may cause significant toxicity, particularly in children. One report from two large pediatric hospitals identified 47 children requiring hospitalization for unintentional clonidine ingestions over a 5-year period.266 Significant clonidine poisoning has also resulted from formulation and dosing errors in children.211,241 Imidazolines used as ocular vasoconstrictors have resulted in significant systemic toxicity, especially when ingested.109,150,137,202

Pharmacology Clonidine and the other centrally acting antihypertensives exert their hypotensive effects primarily via

78,194,218,257 stimulation of presynaptic α2-adrenergic receptors in the brain. This central α2-adrenergic receptor agonism enhances the activity of inhibitory neurons in the vasoregulatory regions of the central nervous system (CNS), notably the nucleus tractus solitarius in the medulla, resulting in decreased norepinephrine release.217 This results in decreased sympathetic outflow from the intermediolateral cell columns of the thoracolumbar spinal tracts into the periphery2,256 and reduces the heart rate, vascular tone, and, ultimately, arterial blood pressure.186,256 This centrally mediated sympatholytic effect is modulated by nitric oxide and γ-aminobutyric acid (GABA), which may explain some of the clinical variability that occurs among patients who have overdosed with clonidine.37,87,234,260

Pharmacokinetics Clonidine is well absorbed from the gastrointestinal (GI) tract (~ 75%) with an onset of action within 30 to 60 minutes. The peak serum concentration occurs at 2 to 3 hours and lasts as long as 8 hours.59 Clonidine has 20% to 40% protein binding and an apparent volume of distribution of 3.2 to 5.6 L/kg.138 The majority of clonidine is eliminated unchanged via the kidneys.143

Clonidine is available in both oral and patch form. The patch, referred to as the clonidine transdermal therapeutic system, allows slow, continuous delivery of drug over a prolonged period of time, typically one week. This formulation, however, offers unique clinical challenges. Each patch contains significantly more drug than is typically delivered during the prescribed duration of use. For example, while a patch that delivers 0.1 mg/day of clonidine contains a total of 2.5 mg, the product that delivers 0.3 mg/day and contains a total of 7.5 mg.36 Even after one week of use, between 35% and 50% and, in some instances, as much as 70%, of the drug remains in the patch.36,98 Puncturing the outer membrane layer or backing opens the drug reservoir and allows a significant amount of the drug to be released rapidly. In addition, patients do not perceive this delivery system as a medication, and they may not exercise appropriate precautions. For example, discarding a used patch in an open wastebasket provides toddlers, who often are fascinated with stickers and other adhesive objects, an opportunity to remove the patch and apply, taste, or ingest it. Numerous reports of toxicity in both adults and children have resulted from dermal exposure, mouthing, or ingesting one clonidine patch, emphasizing this concern.36,47,98,102,124,204,205

Guanabenz and guanfacine are structurally and pharmacologically very similar to each other. They are well absorbed orally, achieving peak concentrations within 3 to 5 hours, and both have large volumes of distribution (4–6 L/kg for guanfacine, 7–17 L/kg for guanabenz).109,237 Whereas guanabenz is metabolized predominantly in the liver and undergoes extensive first-pass effect, guanfacine is eliminated equally by the liver and kidney.109,237 The metabolism of neither drug results in the production of significant active metabolites.

Whereas clonidine, guanabenz, and guanfacine are all active drugs with direct α2-adrenergic agonist effects, methyldopa is a prodrug. It enters the CNS, probably by an active transport mechanism, before it is converted into its pharmacologically active degradation products.22 α- Methylnorepinephrine is the most significant of its metabolites, although α-methyldopamine and α-

75,101,210 methylepinephrine may also be important. These metabolites are direct α2-adrenergic agonists and impart their hypotensive effect as do the other centrally acting antihypertensives. Approximately 50% of an oral dose of methyldopa is absorbed, and peak serum concentrations are achieved in 2 to 3 hours.170However, because methyldopa requires metabolism into its active form, these concentrations have little correlation with its clinical effects. Methyldopa has a small volume of distribution (0.24 L/kg) and little protein binding (15%).170 It is eliminated in the urine, both as parent compound and after hepatic sulfation.179

Pathophysiology In therapeutic oral dosing, clonidine and the other centrally acting antihypertensives have little effect on the peripheral α2 receptors, the peripheral sympathetic nervous system, or the normal circulatory responses that occur with exercise or the Valsalva maneuver.169,183However, when serum concentrations increase above 2 ng/mL, as in the setting of intravenous (IV) administration or oral overdose, peripheral postsynaptic α2-adrenergic stimulation may occur, causing increased norepinephrine release and producing vasoconstriction and hypertension.44,53,173,243 This hypertension is short lived, however, because the potent centrally mediated sympathetic inhibition becomes the predominant effect, and hypotension ensues.4,154,168,210 Imidazoline specific binding sites are identified both in the rostral ventrolateral medulla and in coronary artery vascular smooth muscle and may be important in the clinical effects of these xenobiotics although there exact function has not been elucidated.210,248 Direct stimulation of these imidazoline binding sites appears to lower blood pressure

24,62 independent of central α2-adrenergic effects. Therefore, although their precise physiologic relationship has not been clearly elucidated, more evidence supports the concept that both imidazoline and α2-adrenergic receptors modulate the ability of clonidine, and presumably other centrally acting antihypertensives, to inhibit central norepinephrine release and the cardiovascular effects.25,62,99,163

Clinical Manifestations Although the majority of the published cases involve clonidine, the signs and symptoms of poisoning with any centrally acting antihypertensive are similar. The CNS and cardiovascular toxicity reflect an exaggeration of their pharmacologic action. Common signs include CNS depression, bradycardia, hypotension, and (occasionally) hypothermia.6,192,227,253 Most patients who ingest clonidine or the other similarly acting drugs manifest symptoms rapidly, typically within 30 to 90 minutes.266 The exception may be methyldopa, a prodrug, which requires metabolism to be activated, possibly delaying toxicity for hours.227,270 CNS depression is the most frequent clinical finding and may vary from mild lethargy to coma.149,154,182,203 In addition, severely obtunded patients may experience decreased ventilatory effort and hypoxia.4 Respirations may be slow and shallow, with intermittent deep, sighing breaths. Various other terms are used to describe this phenomenon, including gasping, Cheyne-Stokes respirations, and periodic apnea.6,10,124,154 This hypoventilation is characteristically responsive to tactile stimuli in children, although mechanical ventilation may be required in severe cases.4,6,103,124 The associated CNS depression typically resolves over 12 to 36 hours.10,182 Other manifestations of this CNS depression include hypotonia, hyporeflexia, and irritability.44,154,239 The cranial nerve examination often demonstrates miotic pupils that may remain reactive to light.4,6,245 Two unusual case reports describe seizures in the setting of clonidine poisoning,44,146 the mechanism of which is unclear.

Hypothermia is associated with overdoses involving centrally acting antihypertensives.6,154,192,210 This is thought to be a consequence of α-adrenergic effects within the thermoregulatory center, although other authors suggest that these drugs activate central serotonergic pathways that alter normal thermoregulation.138,161 Although this phenomenon may last several hours, it rarely requires treatment and responds well to passive rewarming.44,192

Sinus bradycardia may occur in up to 50% of patients who ingest clonidine and it results from the combination of an exaggerated centrally mediated sympatholytic effect, a centrally mediated increase in vagal tone, or a direct stimulation of α2-adrenergic receptors on the myocardium.55,132,239,256,266,267

Other conduction abnormalities, including first degree heart block, type 1 and 2 Mobitz atrioventricular block, and complete heart block, are described both in overdose and after therapeutic dosing.123,182,218,220,254,267 It appears that very young patients and patients who have underlying sinus node dysfunction, concurrent sympatholytic drug therapy, or chronic kidney disease (CKD) are at particular risk of developing bradydysrhythmia after central antihypertensive ingestion.31,239,247

Hypotension is the major cardiovascular manifestation of central antihypertensive toxicity.6,36,182,222,239,266 While studies have suggested a dose-response relationship between the history of the quantity of the centrally acting antihypertensive ingested and the severity of the clinical manifestations, clonidine ingestions as small as 0.2 mg have resulted in clinically severe poisoning, mandating the necessity to individually assess each exposure; the presence of any symptoms should prompt immediate medical evaluation.18,182 Fatalities from any of these xenobiotics are rare, with few published reports from the American Association of Poison Control Centers (AAPCC) database29(Chap. 136).

After deaths of four children who were prescribed clonidine were reported, concerns that there was a causal association between combination clonidine–methylphenidate therapy and sudden death were raised.35,71 Fortunately, closer scrutiny of these cases revealed significant confounders, and a formal investigation by the US Food and Drug Administration (FDA) concluded that there was inadequate evidence to confirm this association.71,199,242,266 Withdrawal Abrupt cessation of central antihypertensive therapy may result in withdrawal that is characterized by excessive sympathetic activity. Symptoms include agitation, insomnia, tremor, palpitations, tachycardia, and hypertension, that begin between 16 and 48 hours after cessation of therapy.95,206 Ventricular tachycardia and myocardial infarction may occur in patients with clonidine withdrawal.19,172,193 The frequency and severity of symptoms appear to be greater in patients treated with higher doses for several months and in those with the most severe pretreatment hypertension.206 Shorter-acting drugs such as clonidine and guanabenz are more frequently associated with withdrawal.30,82,201,269 Due to the prolonged and continuous exposures, children being treated with extended release guanfacine formulations and transdermal patches, may be placed at greater risk of developing withdrawal upon cessation. The mechanism for this hyperadrenergic phenomenon appears to involve an increase in CNS noradrenergic activity in the setting of

65 decreased α2-receptor sensitivity. Reasonable treatment strategies include administering clonidine or benzodiazepines, via either the oral or IV route, followed by a closely monitored tapering of the dosing over several weeks. Animal and human data suggest that β-adrenergic antagonists, including labetalol, are contraindicated in clonidine withdrawal.9,117 Esmolol exacerbates this paradoxical hypertension in a manner similar to that which occurs when these xenobiotics are used in cocaine toxicity by inducing unopposed α1-receptor stimulation (Chap. 78).

Diagnostic Testing Clonidine and other centrally acting antihypertensives are not routinely included in serum or urine toxicologic assays. Consequently, management decisions should be based on clinical parameters. No electrolyte or hematologic abnormalities are associated with this exposure. Because of the potential for bradydysrhythmia and hypoventilation, 12-lead electrocardiography (ECG) and continuous cardiac and pulse oximetry monitoring are recommended.

Management Appropriate therapy begins with particular focus on the patient’s respiratory and hemodynamic status. Administration of activated charcoal (AC) is the primary mode of GI decontamination in most cases of ingestion. Patients often present after the onset of symptoms rather than immediately after ingestion, and patients respond well to supportive care. In cases involving clonidine patch ingestions, whole-bowel irrigation appears to be an effective intervention.102

All patients with CNS depression should be evaluated for hypoxia and hypoglycemia. Those with respiratory compromise, including apnea, often respond well to simple auditory or tactile stimulation.4,6,103,124 Significant arousal during preparation for intubation often precludes the need for mechanical ventilation.4 Endotracheal intubation should be performed if clinically indicated.

Patients with isolated hypotension should initially be treated with IV boluses of crystalloid: 20 mL/kg in children and 500 to 1000 mL in adults. Bradycardia is typically mild and usually does not require any therapy if adequate peripheral perfusion exists. If the symptomatic bradycardia occurs, then atropine is often effective and redosing may be required.4,6,149,239 It is likely that naloxone was first used in clonidine-poisoned patients because of their clinical findings of CNS and respiratory depression and miosis is similar to opioid-poisoned patients.174 Clonidine-poisoned patients, particularly children, may have increased arousal, respiratory effort, heart rate, and blood pressure after naloxone administration.10,129,174,245 The mechanism for this may relate to modulation of CNS sympathetic outflow by endogenous CNS opioids.26,70,116,222

This concept is supported by a clinical study in which clonidine administration to hypertensive patients for 3 days resulted in a significant decrease in blood pressure. Subsequent administration of 0.4 mg of naloxone parenterally reversed the decrease in blood pressure and heart rate in almost 60% of the patients.69 Because of the short duration of effects of naloxone (20–60 minutes) redosing or continuous infusion may be required. As with some synthetic opioids, such as propoxyphene and fentanyl, clinical improvement may occur only after high doses (4–10 mg) of naloxone,124,152 and some patients have no response regardless of dose used.149,266

Early onset hypertension is typically self limited and therapy should be cautiously undertaken. If hypertension is severe or prolonged, then treatment with a short acting and titratable antihypertensive such as IV nicardipine and sodium nitroprusside is appropriate.154 Esmolol may exacerbate this paradoxical hypertension in a manner similar to that which occurs when these xenobiotics are used in cocaine toxicity by inducing unopposed α1-receptor stimulation (Chap. 78). Although oral nifedipine has been used,58its inability to titrate and its unpredictable efficacy make its use inappropriate as well.

CENTRAL IMIDAZOLINE AGONISTS

Moxonidine and related rilmenidine are also known as second-generation centrally acting antihypertensives and are the newest class of antihypertensives available in the United

62 States. They are structurally similar to clonidine, but selectively attach at I1-imidazoline binding sites which are found predominantly in the rostral ventrolateral medulla, and they have much less affinity

66 for the α2-adrenergic receptor. The exact molecular structure of these imidazoline binding sites has not been determined nor has the exact physiologic cascade or effect of ligand binding at these sites. Therefore these sites are not currently termed “receptors.” Although the exact mechanism of action is still being investigated, binding at these I1-imidazoline specific sites ultimately leads to sympathetic outflow from the medulla, vasodilation, and reduction in blood pressure. Nitric oxide or GABA mechanisms may be involved in their central effects.190,191 Therapeutically, moxonidine is used both as monotherapy or in combination with the antihypertensives. Patients with diabetes or metabolic syndrome may particularly benefit from moxonidine because of its positive effects on insulin resistance, impaired glucose tolerance, and hyperlipidemia.62,72There is one published overdose resulted in initial hypertension and somnolence suggesting that weak α2-adrenergic receptor affinity is overwhelmed in overdose.148 This patient subsequently had two seizures that were responsive to benzodiazepines however never developed any hypotension.148 OTHER SYMPATHOLYTIC ANTIHYPERTENSIVES

Several other xenobiotics also exert their antihypertensive effect by decreasing the effects of the sympathetic nervous system. Often termed sympatholytics, they can be classified as ganglionic blockers, presynaptic adrenergic blockers, or α1-adrenergic antagonists, depending on their mechanism of action. These drugs are rarely used clinically, and little is known about their effects in overdose.

Presynaptic Adrenergic Antagonists

These xenobiotics exert their sympatholytic action by decreasing norepinephrine release from presynaptic nerve terminals. Whereas guanethidine and guanadrel interfere with the action potential that triggers norepinephrine release,224 reserpine depletes norepinephrine, serotonin, and other catecholamines from the presynaptic nerve terminals, probably by direct binding and inactivation of catecholamine storage vesicles.84Adverse events limit their clinical usefulness. These effects include a high incidence of orthostatic and exercise-induced hypotension, diarrhea, increased gastric secretions, and impotence.179 In addition, this hypotensive effect may be prolonged for as long as one week.119,225 Because of its ability to cross the blood–brain barrier, reserpine may also deplete central catecholamines and produce drowsiness, extrapyramidal symptoms, hallucinations, migraine headaches, or depression.142 In overdose, an extension of their pharmacologic effects is expected. Patients with severe orthostatic hypotension should be anticipated and treated with IV crystalloid boluses and a direct-acting vasopressor. If reserpine is involved, significant CNS depression should also be anticipated.142

Peripheral α1-Adrenergic Antagonists

The selective α1-adrenergic antagonists include prazosin, terazosin, and doxazosin. The α1 receptor is a postsynaptic receptor primarily located on vascular smooth muscle, although they are also found in the eye and in the GI and genitourinary tracts.49,107 In fact, these xenobiotics provide first line pharmacologic therapy for patients with urinary dysfunction secondary to benign prostatic hyperplasia.136 They produce arterial smooth muscle relaxation, vasodilation, and a reduction of the blood pressure. Although better tolerated than ganglionic blockers and peripheral adrenergic neuron blockers, they may still produce significant symptoms of postural hypotension, including lightheadedness, syncope, or palpitations, particularly after the first dose or if the dosing is rapidly increased.17 Hypotension and CNS depression ranging from lethargy to coma are reported in overdose.135,140,216 In addition, priapism may occur.140,208 Treatment includes supportive care, IV crystalloid boluses, and a vasopressor, with phenylephrine being a logical initial choice.

Direct Vasodilators

Hydralazine, Minoxidil, and Diazoxide. These xenobiotics produce vascular smooth muscle relaxation independent of innervation or known pharmacologic receptors.60,118,126 This vasodilatory effect has been attributed to stimulation of nitric oxide release from vascular endothelial cells. The nitric oxide then diffuses into the underlying smooth muscle cells, stimulating guanylate cyclase to produce cyclic guanosine monophosphate (cGMP). This second messenger indirectly inhibits calcium entry into the smooth muscle cells, producing vasodilation.215 Minoxidil, however, also has direct potassium channel activation effects.128,176 It has been proposed that the opening of these adenosine triphosphate linked potassium channels results in potassium influx and cell depolarization, thereby reducing calcium influx and ultimately relaxing vascular smooth muscle.33

As this vasodilation occurs, the baroreceptor reflexes, which remain intact, produce an increased sympathetic outflow to the myocardium, resulting in an increase in heart rate and contractile force. Typically, these xenobiotics are used therapeutically in patients with severe, refractory hypertension and in conjunction with a β-adrenergic antagonist to diminish reflex tachycardia. Hydralazine, minoxidil, and diazoxide are effective orally, but sodium nitroprusside is only used IV. Minoxidil is also used topically in a 2% solution to promote hair growth, and significant poisoning has occurred in suicidal adults who have ingested this formulation.68,160 Diazoxide, although previously used to rapidly reduce blood pressure in hypertensive emergencies, is rarely used for this indication now as a consequence of its poor ability to titrate and its variable, and occasionally profound, hypotensive effect.125

Adverse effects associated with daily hydralazine use include several immunologic phenomena such as hemolytic anemia, vasculitis, acute glomerulonephritis, and most notably a lupuslike syndrome.196 Minoxidil may cause changes on ECG, both in therapeutic doses and in overdose. Sinus tachycardia, ST segment depression, and T-wave inversion are all reported.94,198,232 There also appears to be an association with supratherapeutic doses of minoxidil and left ventricular multifocal, subacute necrosis, and subsequent fibrosis.96,97 The significance of either of these changes is unknown; they typically resolve with either continued therapy or as other toxic manifestations resolve.94,97,232

The common toxic manifestations of these xenobiotics in overdose are an extension of their pharmacologic action. Symptoms may include lightheadedness, syncope, palpitations, and nausea.3,147 Signs may be isolated to tachycardia alone,198,232 flushing, or alterations in mental status, which is related to the degree of hypotension.160 Based on AAPCC annual poison data, in recent years, the majority of reported exposures to this class of drugs may have involved the topical formulation of minoxidil29 (Chap. 136).

After appropriate GI decontamination, routine supportive care should be performed with special consideration to maintaining adequate mean arterial pressure. If IV crystalloid boluses are insufficient, then a peripherally acting α-adrenergic agonist, such as norepinephrine or phenylephrine, is an appropriate next therapy. Dopamine andepinephrine should be avoided to prevent an exaggerated myocardial response and tachycardia from β-adrenergic stimulation. Nitroprusside. Sodium nitroprusside is effectively a prodrug, exerting its vasodilatory effects only after its breakdown and the release of nitric oxide. The nitroprusside molecule also contains five cyanide radicals that, although gradually released, occasionally produce cyanide or thiocyanate toxicity.178,219 Physiologic methemoglobin can bind the liberated cyanide. The binding capacity of physiologic methemoglobin is about 175 µg/kg of cyanide, corresponding to a little less than 500 µg/kg of infused sodium nitroprusside. These cyanide moieties are rapidly cleared, both by interacting with various sulfhydryl groups in the surrounding tissues and blood and enzymatically in the liver by rhodanese, which couples them to thiosulfate-producing thiocyanate.76 This cyanide detoxification process in healthy adults occurs at a rate of about 1 µg/kg/min, which corresponds to a sodium nitroprusside infusion rate of 2 µg/kg/min.51,219 It is limited by the sulfur donor availability, so factors that reduce these stores, such as poor nutrition in infants and toddlers, critical illness, surgery, and diuretic use, place patients at risk for developing cyanide toxicity.40,51The hemolysis associated with cardiopulmonary bypass may place the patient at particular risk because the elevated free hemoglobin may accelerate the release of cyanide from the sodium nitroprusside moiety.40 Therefore, depending on the balance of cyanide release (eg, rate of sodium nitroprusside infusion) and the rate of cyanide detoxification (eg, sulfur donor stores), cyanide toxicity may develop within hours. Infusion rates greater than 4 µg/kg/min of nitroprusside for greater than 12 hours may overwhelm the capacity of rhodanese for detoxifying cyanide.207 Signs and symptoms of cyanide toxicity include alteration in mental status; anion gap metabolic acidosis; and in late stages, hemodynamic instability. If cyanide poisoning does occur, then hydroxycobalamin is the current treatment of choice for treatment (Chap. 126).

One method of preventing cyanide toxicity from sodium nitroprusside is to expand the thiosulfate pool available for detoxification by the concomitant administration of sodium thiosulfate.51,92,164,219 Dosing of 1 g sodium thiosulfate for every 100 mg of nitroprusside is typically sufficient to prevent cyanide accumulation.207 Unfortunately, the thiocyanate formed may accumulate, particularly in patients with renal insufficiency, and produce thiocyanate toxicity.76,219 Simultaneous infusion of thiosulfate does not interfere with the vasodilatory effects of sodium nitroprusside.104 Needless to say, the potential of sodium nitroprusside to produce cyanide poisoning, in addition to the introduction of other equally effective and rapidly titratable antihypertensives, has greatly reduced its use.

Thiocyanate is almost exclusively renally eliminated, with an elimination half-life of 3 to 7 days. It is postulated that a continuous sodium nitroprusside infusion of 2.5 µg/kg/min in patients with normal renal function could produce thiocyanate toxicity within 7 to 14 days, although it may be as short as 3 to 6 days or as little as 1 µg/kg/min in patients with CKD who are not receiving hemodialysis.219 The symptoms of thiocyanate toxicity begin to appear at serum concentrations of 60 µg/mL (1 mmol/L); are very nonspecific; and they may include nausea, vomiting, fatigue, dizziness, confusion, delirium, and seizures.76Thiocyanate toxicity may produce life-threatening effects, such as hemodynamic and intracranial pressure elevation, when serum concentrations are above 200 µg/mL.51,76,92,249 Anion gap metabolic acidosis and hemodynamic instability do not occur with thiocyanate toxicity. Although cyanide or thiocyanate concentrations are not typically useful in the management of patients with cyanide toxicity, they may be beneficial for monitoring critically ill patients who are at risk of thiocyanate poisoning. Hemodialysis clears thiocyanate from the serum and should be strongly considered in patients with significant clinical manifestations of thiocyanate toxicity.64,153,166

Another therapy used to prevent cyanide toxicity from sodium nitroprusside is a simultaneous infusion of hydroxocobalamin.128 Dosing of 25 mg/h has successfully reduced cyanide poisoning in humans.48,270 As with thiosulfate, simultaneous infusion ofhydroxocobalamin does not interfere with the vasodilatory effects of sodium nitroprusside.104 Because of the relative higher cost of hydroxocobalamin as well its interactions with some laboratory tests, thiosulfate should remain the mainstay of prophylaxis against sodium nitroprusside-induced cyanide toxicity (Antidotes in Depth: A40 and A41).

Diuretics Diuretics can be divided into three main groups: (1) the thiazides and related compounds, including hydrochlorothiazide and chlorthalidone, (2) the loop diuretics, including furosemide, bumetanide, and ethacrynic acid, and (3) the potassium-sparing diuretics, including amiloride, triamterene, and spironolactone. Two other groups of diuretics—the carbonic anhydrase inhibitors, such as acetazolamide, and osmotic diuretics (eg, mannitol)—are not used as antihypertensive agents.

The thiazides produce their diuretic effect by inhibition of sodium and chloride reabsorption in the distal convoluted tubule. Loop diuretics, in contrast, inhibit the coupled transport of sodium, potassium, and chloride in the thick ascending limb of the loop of Henle. Although their exact antihypertensive mechanism is unclear, an increased urinary excretion of sodium, potassium, and magnesium results from the use of loop diuretics. Potassium-sparing diuretics act either as aldosterone antagonists, such asspironolactone, or as renal epithelial sodium channel antagonists, such as triamterene, in the late distal tubule and collecting duct.114

The majority of toxicity associated with diuretics is metabolic and occurs during chronic therapy or overuse.264 Hyponatremia develops within the first 2 weeks of initiation of diuretic therapy in more than 67% of susceptible patients, and female sex, old age, and malnourishment are the greatest risk factors.8,235 Symptoms of severe hyponatremia (< 120 mEq/L) may include headache, nausea, vomiting, confusion, seizures, or coma (Chap. 19). The osmotic demyelination syndrome, formally known as central pontine myelinolysis, is reported during rapid correction of severe hyponatremia secondary to diuretic abuse.46

Other electrolyte abnormalities associated with diuretic use include hypokalemia and hypomagnesemia, which may precipitate ventricular dysrhythmias such as torsade de pointes and sudden death. This is an extremely controversial topic, with several excellent studies providing conflicting results.21,77,185,228,230 Although it is unclear how great a risk, if any, diuretic use may be, it remains prudent to monitor and correct the patient’s potassium concentration.108,228,262 This is particularly important in elderly patients and for those patients who concomitantly use digoxin, in which setting hypokalemia is clearly associated with dysrhythmias (Chap. 65).28,240 Potassium-sparing diuretics may cause hyperkalemia, particularly in the setting of renal insufficiency or when combined with other hyperkalemia-producing drugs such as ACEIs.118

Thiazide diuretics are associated with inducing hyperglycemia, particularly in patients with diabetes mellitus. This is a result of depletion of total body potassium stores. Because insulin secretion is dependent on transmembrane potassium fluxes, this decrease in potassium concentration reduces the amount of insulin secreted.144 This effect is dose dependent and reversible either by potassium supplementation or discontinuation of the thiazide diuretic.39,100 This association has lead to significant work and discussion about the routine use of thiazide diuretics as first-line antihypertensives in the treatment of uncomplicated patients.52,90,166 In addition, thiazides are less well tolerated than any other antihypertensive drug class leading to significant noncompliance.165

Thiazide diuretics are also associated with inducing hyperuricemia, renal calculi, and gout.34,91,93 This is because the renal elimination of uric acid is extremely dependent on intravascular and urinary volume so diuretic-induced volume depletion reduces uric acid filtration and increases its proximal tubule resorption.226,238

Several unusual reactions are associated with thiazide diuretic use, including pancreatitis; cholecystitis; and hematologic abnormalities, such as hypercoagulability, thrombocytopenia, and hemolytic anemia.61,63,212,214,252,261

Despite the widespread use of these xenobiotics, acute overdoses are distinctly rare.139Major signs and symptoms include GI distress, brisk diuresis, possible hypovolemia and electrolyte abnormalities, and altered mental status.139 Typically, the diuresis is short lived because of the limited duration of effect and the rapid clearance of the majority of diuretics. Assessment should focus on fluid and electrolyte status, which should be corrected as needed. If hyperkalemia is unexpectedly discovered, either the ingestion of a potassium-sparing xenobiotic or, more likely, an overdose of potassium supplements, which are frequently prescribed in conjunction with thiazide and loop diuretics, should be considered.111,112 Altered mental status, including coma, may result from diuretic overdose without evidence of any fluid or electrolyte abnormalities.17,18,139,213 Postulated mechanisms include a direct drug effect and induction of transient cerebral ischemia due to hypotension.180

Angiotensin-Converting Enzyme Inhibitors ACEIs are among the most widely prescribed antihypertensives. At the time of this writing, there are 10 ACEIs approved by the US FDA for the treatment of hypertension (Table 63–1). In general, they are well absorbed from the GI tract, reaching peak serum concentrations within 1 to 4 hours. Enalapril and ramipril are prodrugs and require hepatic metabolism to produce their active forms. Elimination is primarily via the kidneys.

TABLE 63–1. Antihypertensives and Pharmacologically Related Agents View Large | Favorite Table All ACEIs have a common core structure of a 2-methylpropanolol-L-proline moiety.81 This structure binds directly to the active site of ACE, which is found in the lung and vascular endothelium, preventing the conversion of angiotensin I to angiotensin II. Because angiotensin II is a potent vasoconstrictor and stimulant of aldosterone secretion, vasodilation; decreased peripheral vascular resistance; decreased blood pressure; increased cardiac output; and a relative increase in renal, cerebral, and coronary blood flow occur.81 This hypotensive response may be severe in select patients after their initial dose, resulting in syncope and cardiac ischemia.42,106 Patients with renovascular-induced hypertension and patients who are hypovolemic from concomitant diuretic use appear to be at greatest risk.106 Overall, however, these drugs are well tolerated and have a very low incidence of side effects. Some reported adverse effects include rash, dysgeusia, neutropenia, hyperkalemia, chronic cough, and angioedema.56,81,246 Because of their interference with the renin– angiotensin system, ACEIs are potential teratogens and should never be used by pregnant women or women of childbearing age.13

ACEI-Induced Angioedema. Angioedema is an inflammatory reaction in which there is increased capillary blood flow and permeability, resulting in an increase in interstitial fluid. If this process is confined to the superficial dermis, urticaria develops; if the deeper layers of the dermis or subcutaneous tissue are involved, angioedema results. Angioedema most commonly involves the periorbital, perioral, or oropharyngeal tissues.199 This swelling may progress rapidly over minutes and result in complete airway obstruction and death.80,85,223 The pathogenesis of acquired angioedema involves multiple vasoactive substances,

110 including histamine, prostaglandin D2, leukotrienes, and bradykinin. Because ACE also inactivates bradykinin and substance P, ACE inhibition results in elevations in bradykinin concentrations that appear to be the primary cause of both ACEI angioedema and cough (Fig. 63–1).5,113 There is no evidence that the ACEI angioedema phenomenon is immunoglobulin E (IgE) mediated.5

FIGURE 63–1. An overview of the normal function of the renin-angiotensin-aldosterone system (RAAS) and the mechanisms of action of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and direct renin inhibitors (DRIs) on that system. PVR = peripheral vascular resistance.

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Although the literature is replete with reports of ACEI angioedema, the overall incidence is only approximately 0.1%, and it is idiosyncratic.73,113,231 One-third of these reactions occur within hours of the first dose and another third occur within the first week.151,231 It is important to remember that the remaining third of cases may occur at any time during therapy, even after years.41 Women, African Americans, and patients with a history of idiopathic angioedema appear to be at greater risk.151,184 In addition, there is evidence that patients who develop ACEI angioedema are at increased subsequent risk of developing angioedema from any etiology.16 Treatment varies depending on the severity and rapidity of the swelling. Because of its propensity to involve the tongue, face, and oropharynx, the airway must remain the primary focus of management. A nasopharyngeal airway is often helpful. If there is any potential for or suggestion of airway compromise, then endotracheal intubation should be performed. Severe tongue and oropharyngeal swelling may make orotracheal or nasotracheal intubation extremely difficult, if not impossible. If this is a concern, then fiberoptic nasal intubation may be an attractive option, provided that the resources are available. Other techniques, including retrograde intubation over a guidewire that was passed through the cricothyroid membrane and emergent cricothyrotomy, may also be considered.207 However, the most important aspect of airway management in patients experiencing ACEI angioedema is early risk assessment for airway obstruction and rapid intervention before the development of severe and obstructive swelling.2

Because ACEI angioedema is not an IgE-mediated phenomenon pharmacologic therapy targeting an allergic cascade, such as epinephrine, diphenhydramine, and corticosteroids, should not be expected to be effective. However, when the history is unclear, these medications should not be withheld in order to ensure providing life-saving therapy to someone having a severe IgE-mediated allergic reaction.

Newer treatment modalities developed to target various points along the cascade of events associated with hereditary angioedema may be beneficial in the treatment of ACEI angioedema. Hereditary angioedema results from a genetically mediated defect in C1 inhibitor resulting in limited activity of this enzyme and an increase in kallikrein concentrations. Kallikrein is a protease that cleaves kininogen into bradykinin. The end result is very similar to the cause of ACEI angioedema, namely an activation of vascular bradykinin B2 receptors.13 Several new treatments have been developed to target specific steps in the development of hereditary angioedema, including Berinert, a C1 esterase inhibitor, ecallantide, a kallikrein inhibitor, and icatibant, a bradykinin B2 receptor antagonist. Case reports of successful treatment of ACEI angioedema with these xenobiotics are few.14,79,177 However, one case series of eight patients with ACEI angioedema who where treated with 30 mg subcutaneous icatibant had more rapid improvement in their signs and symptoms as well as no need for subsequent steroid ordiphenhydramine use.14 While further evidence is needed, icatibant may be a reasonable treatment for ACEI angioedema; however, its significant cost should limit its use only in patients with rapidly progressive or severe angioedema.

Fresh frozen plasma (FFP) which contains ACE has also been proposed as treatment for ACEI angioedema. FFP infusion will elevate ACE concentrations and lead to the degradation of accumulated bradykinin. Clinical use of FFP for the successful treatment of both hereditary and ACEI angioedema is reported.122,189,200,263 In these case reports, doses range from 1 to 5 units of FFP (200–250 mL/unit) with most using an infusion of 2 units of FFP as initial, and typically definitive, treatment.200

All patients with mild or rapidly resolving angioedema should be observed for several hours to ensure that the swelling does not progress or return. Outpatient therapy with a short course of oral antihistamines and corticosteroids should be considered if there is any question as to whether ACEI therapy produced the angioedema because allergic-mediated angioedema will benefit from this treatment. Patients developing angioedema from ACEI therapy should be instructed to discontinue them permanently and to consult their primary care physicians about other antihypertensive options. Because this is a mechanistic and not allergic adverse effect, the use of any other ACEIs is contraindicated.

Angiotensin-Converting Enzyme Inhibitor Overdose. The toxicity of ACEIs in overdose appears to be limited.43,141 Although several reports of overdoses involving ACEIs are published, the majority of the cases reported manifested toxicity of a coingestant.54,89,262 Hypotension may occur in select patients,11,12,131 but deaths are rarely reported in isolated ACEI ingestions.187,235 Other patients may remain asymptomatic despite high serum drug concentrations.131

Treatment should focus on supportive care and on identifying any coingestants that may be more toxic, particularly other antihypertensives such as β-adrenergic antagonists and calcium channel blockers. In most cases, AC alone is sufficient GI decontamination. IV crystalloid boluses are often effective in correcting hypotension, although in rare cases, catecholamines may be required.7,83 Naloxone may also be effective in reversing the hypotensive effects of ACEIs. ACEIs may inhibit the metabolism of enkephalins and potentiate their opioid effects, which include lowering blood pressure.57,167 In a controlled human volunteer study, continuous naloxone infusion effectively blunted the hypotensive response of captopril.1 In one case report, naloxone appeared to be effective in reversing symptomatic hypotension secondary to a captopril overdose.258 In another published case, naloxone was ineffective.11 Although its role in the setting of ACEI overdose remains unclear, naloxone may obviate the need for large quantities of crystalloid or vasopressors and should therefore be considered.

Angiotensin II Receptor Blockers ARBs were first introduced in 1995, and currently, six members of this class are marketed in the United States. These xenobiotics are rapidly absorbed from the GI tract, reaching peak serum concentrations in 1 to 4 hours, and then are eliminated either unchanged in the feces or after undergoing hepatic metabolism via the mixed function oxidase system eliminated in the bile.156,157,158, and 159,181

Although these xenobiotics are similar to ACEIs in that they decrease the effects of angiotensin II rather than decrease the formation of angiotensin II, they act by antagonizing angiotensin II at the type 1 angiotensin (AT-1) receptor (Fig. 63–1).123 This allows the drugs to inhibit the vasoconstrictive- and aldosterone-promoting effects of angiotensin II and reduce blood pressor by blunting both the sympathetic as well as the renin–angiotensin systems.156 Despite the mechanistic evidence that ARBs do not affect bradykinin degradation and therefore should have a much lower incidence of angioedema when compared to ACEIs, serious cases of angioedema associated with ARB therapy have been reported.38,151,255 In addition, there is a significantly higher incidence of angioedema associated with ARBs when compared to other antihypertensives, such a β-adrenergic antagonists.250 Similar to ACEIs, ARBs should never be used by pregnant patients because of their teratogenic potential.13,229 In addition, when initiating the xenobiotic, up to 1% develop of patients first-dose orthostatic hypotension.86

There have been few published reports of overdoses involving ARBs. Adverse signs and symptoms reflect orthostatic or absolute hypotension and include palpitations, diaphoresis, dizziness, lethargy, or confusion.74,162,233 Hypotension should be treated with crystalloid boluses and catecholamine therapy.162,233 Patients who are chronically taking ARBs may exhibit significant hypotension during induction of general anesthesia that has been refractory to traditional vasoconstrictor therapy, such as norepinephrine, ephedrine, and phenylephrine, but appear to respond to vasopressin.23,27,67

One promising new treatment for hypotension produced by ARBs and ACEIs is methylene blue.155,171,251 This treatment was first explored in patients placed on cardiopulmonary bypass (CPB).186,236,251 During CPB systemic blood pressure and peripheral vascular resistance decrease due to a number of factors, including acute hemodilution, citrate use in the cardioplegia, a poorly defined inflammatory response that results in nitric oxide release, and an increase in circulating bradykinin.45,50,268 This increase in bradykinin, which also mediates its vasodilatory effects via nitric oxide, occurs because bradykinin metabolism is primarily in pulmonary tissue and CPB mechanically bypasses the pulmonary system.45,50 ACEIs and ARBs exacerbate this vasodilation by inhibiting bradykinin metabolism.197 In a double blinded placebo controlled study of 30 patients taking ACEIs who were undergoing elective cardiac surgery requiring CPB, administration of methylene blue at the onset of CPB resulted in an increase in mean arterial pressure and systemic vascular resistance and less use of phenylephrine and norepinephrine.155 A reasonable starting dose of methylene blue, when used as a vasopressor, appears to be 2 mg/kg with subsequent intermittent boluses or possibly continuous infusions starting at 0.5 mg/kg/h.115,155

DIRECT RENIN INHIBITORS

Direct renin inhibitors (DRIs) such as aliskiren exert their antihypertensive effects via the renin- angiotensin-aldosterone system (RAAS) by directly inhibiting circulating renin.265Unfortunately, all RAAS acting antihypertensives such as ACEIs, ARBs, and DRIs induce a compensatory increase in serum renin concentrations; however, only DRIs are able to blunt the physiologic effects of this rise.32,221,265 Aliskiren is well tolerated and is an effective antihypertensive both as monotherapy and in combination with other antihypertensives, including hydrochlorothiazide, calcium channel blockers, and β-adrenergic antagonists.144 However, significant controversy surrounds aliskiren use when combined ARBs or ACEIs after a clinical trial was halted due to an increased incidence of ischemic stroke, acute kidney injury, hyperkalemia, and hypotension was noted in patients with diabetes and CKD.188 There are no reported cases of poisoning or overdose; however, hypotension should be anticipated and treatment that includes supportive care, including IV crystalloid and catecholamines, seems reasonable. SUMMARY

 These xenobiotics are not often associated with severe poisonings, either because of limited use, as with most of the sympatholytics and direct vasodilators, or because of limited toxicity, as with diuretics, ACEIs, ARBs, and DRIs.

 Severe clonidine poisoning classically presents as the opioid toxidrome producing profound CNS depression and bradycardia.

 Clonidine withdrawal manifests as CNS agitation, tachycardia, and hypertension and should be treated with clonidine or benzodiazepines.

 Nitroprusside infusions greater than 4 µg/kg/min may result in cyanide poisoning which can be prevented with coadministration of thiosulfate or hydroxycobalamin.

 Because of the pathogenesis of ACEI-induced angioedema, it is unlikely to respond to “typical” allergic treatment such as antihistamines, epinephrine, and steroids. Rather, focus should be on definitive airway management in patients with rapidly progressing swelling or symptoms.

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